The long range objective of this work is to develop a better method to preserve the human liver for transplantation. The consequences of this would be: more livers available for patients dying from end stage liver diseases, a decrease in the number of transplanted livers that develop primary non-function or delayed graft function, increase in capabilities for national (or international) sharing of cadaveric livers, a decrease in the cost of liver transplantation by reducing the need for retransplantation and the length of hospital (ICU) stay of the patient. Currently, the University of Wisconsin (UW) solution is the standard preservation solution for liver preservation. We will use this solution as the basis for developing improved preservation solutions and methods of preservation (simple cold storage and continuous machine perfusion). The specific aims of this study are to gain an understanding of the mechanisms of cellular injury caused by hypothermic storage of the liver and with this knowledge develop improved preservation methods. We will study the mechanisms of hypothermic injury using a rat hepatocyte and rabbit liver isolated perfusion model. We will study how precursors of ATP and glutathione synthesis affect preservation, the role of calcium and phospholipid lipases in preservation injury and how various drugs affect the preservation of the liver. Additionally, we will gain insight into the mechanism of preservation injury by investigating the importance of the various components of the UW solution and how the addition of different drugs and metabolites to the UW solution affect the quality and duration of liver preservation. We will determine how preservation affects the energy generating capabilities of the liver and how oxygen free radical scavengers affect preservation quality. We will also study how donor factors affect liver preservation, specifically the nutritional status of the donor. Methods that improve liver cell metabolism and liver functions will be tested in the dog orthotopic transplant model to determine if these methods translate to a more clinically relevant model of liver preservation. Methods that improve liver preservation in the laboratory will be used for human liver preservation.